Traditional cancer-treating methods, including radiotherapy, chemotherapy and the electrotherapy for some local solid tumors, have considerable curative effect. However, they also have significant toxic side effect and cause severe pain for patients during the course of treatment.
Most tumors are solid tumors. Their generation, development, recurrence, and transfer all depend on the angiogenesis of tumors, which is an absolutely necessary condition for the growth and transfer of solid tumors. The starvation therapy, which is to inhibit tumor angiogenesis and block the supply of blood for tumor tissues, is considered as one of the most perspective new methods for treating the solid tumor.
The normal construction of tissues and the maintenance of their functions depend on a multistep cell membrane signal transduction from the cell environment to nucleolus in order to transcript and regulate genes. Cancer is an abnormal cell activity caused by a maladjusted signal transduction pathway, for instance, changes in cell growth, survival and functionality and the loss of capability of differentiation. Tumors' growth relies on their autoecious competence in hosts and the angiogenesis to use the nutrition and oxygen of hosts. The development of solid tumors relies on a tumor-generated growth factor, which activates the signal response of endotheliocyte in hosts and extends the tumor blood vessel systems from the existing blood vessels (angiogenesis). The formation rate of adult blood vessels is rather slow and only the endometrium has normal activity of proliferation. The approach of targeted block of angiogenesis is an effective treatment for the pathologic angiogenesis in tumor tissues.
VEGF (Vascular Endothelial Growth Factor), closely relating to the development of solid tumors, is a vascular growth factor in the formation of tumor blood vessels and plays a role in hormonal regulation of the differentiation of endotheliocytes. According to prior research results, many diseases including malignant tumors are related to angiogenesis (Fan, et al, 1995, Trends Pharmacol. Sci. 16, 57-66; Folkman, 1995, Nature Medicinel, 27-31). The change of vascular permeability is thought to play a certain role in both normal and pathologic physiological courses (Cullinan-Bove, et al, 1993, Endocrinology 133, 829-837; Senger, et al, 1993, Cancer and Metastasis Reviews. 12, 303-324). VEGF is an important stimulating factor for the normal and pathological formation of blood vessel and the change of vascular permeability (Jakeman, et al, 1993, Endocrinology 133, 848-859; Kolch, et al, 1995, Breast Cancer Research and Treatment, 36, 139-155; Connolly, et al, 1989, J. Biol. Chem. 264, 20017-20024). The antagonistic action caused by sequestration of VEGF by antibody can inhibit tumor growth (Kim, 1993, Nature 362, 841-844).
The increase in expression of VEGF is the result of stimulation by multiple factors, including the activation of oncogenes and hypoxemia, which can be caused in solid tumors because of the improper perfusion of tumor patients. Besides promoting the angiogenesis, VEGF can also improve the permeability of vascular walls, speed up the exchange of nutrition and metabolite between the tumor and contiguous tissues and reduce the natural barrier of vascular walls to make possible the remote transfer of tumor.
VEGF, via binding to tyrosine kinases (TKs), activates the corresponding signal transduction pathway and stimulate the formation and proliferation of new tumor blood vessels. The RTKs (receptor tyrosine kinases) activated by the combination of VEGF and its receptor play a vital role in the transmembrane signal transduction pathway and thus influence the growth and transfer of tumor. These transmembrane molecules are characterized in that they consist of the extracellular ligand-binding domain linked with the intracellular TKs region through segments in the plasma membrane. The combination of ligand and receptor stimulates the activity of receptor-related TKs and causes the phosphorylation of the tyrosine residues in the receptor and other molecules. The changes of the tyrosine phosphorylation induce a signal cascade and produce numerous cell responses. So far, at least 19 different RTK sub-families have been identified according to the homology of amino acid sequence, one of which contains the TK receptor Flt or Flt1 similar to fms, the receptor KDR (also called Flk-1) with kinase insertion domains and another TK receptor Flt4 similar to fms. It has been proved that two of the correlative RTKs, Flt and KDR can combine with VEGF with high affinity (De Vries, et al, 1992, Science 255, 989-991; Terman, et al, 1992, Boichem. Biophys. Res. Comm., 1992, 187, 1579-1586). The combination of VEGF and the receptor expressed in heterogeneous cells correlates to the tyrosine phosphorylation level of cell proteins and changes of calcium current.
The above discussed research has proved that VEGF is a specific, direct key positive regulator of vascular endothelial cells in the course of angiogenesis of solid tumors. The KDR/Flk-1 pathway between VEGF and its receptor has become one of the main targets of anti-tumor blood vessel therapy. The inhibition of the activity of TKs is an important means to block tumor angiogenesis.